| Abstract |
This proposal focuses on a therapeutic inhibitor to human papillomavirus (HPV), an AIDS-associated opportunistic infection. The vast majority of cervical and anogenital cancers are caused by HPV infection. HIV-infected individuals are particularly susceptible to developing papillomavirus infections and associated malignancies. HPV infection is also a major problem in the general population. This year 3 million women in the U.S. will develop cervical dysplasia, the premalignant condition that can progress to cervical cancer. Prophylactic HPV vaccines have shown exciting results although they are not used for treatment of an existing infection. Comparatively, an effective therapeutic anti-HPV agent will immediately reduce the development of cervical and anal squamous carcinomas, particularly in the immune-compromised HIV-infected population. The key regulator of viral transcription and replication is the viral E2 protein, which has an N-terminal activation domain and a C-terminal dimerization domain. A repressor form of E2 that lacks the N-terminal activation domain is an inhibitor in cell culture. By using structure-based protein design, we have refined the inhibitor in vitro. In a new interdisciplinary project, we will test this inhibitor using a 3D human tissue model that supports the entire HPV life-cycle. We will generate 3D human, epithelial tissues as “surrogates” for the current and future studies on mechanisms through which viral E2 protein regulates HPV expression and on approaches to HPV eradication. Our hypothesis is that the inhibitors are efficacious and therefore of clinical relevance. We will assess pharmacologic properties, including cellular uptake, half-life, and toxicity and cell and tissue morphology and correlate these properties with results for inhibition of cell proliferation and viral replication. The overall goal is to achieve high potency in tissue-based models for eventual testing in animals. The final product is expected to effectively treat existing benign, pre-malignant, and cancerous stages of HPV-induced diseases that will reduce the incidence of cervical, anal and oropharyngeal dysplasias and the associated carcinomas that afflict millions of women and men each year.
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